Dataset Information

Characterization and immunotherapeutic implications for a novel antibody targeting interleukin (IL)-13 receptor ?2.

ABSTRACT: The high affinity interleukin-13 receptor ?2 (IL13R?2) is selectively expressed at a high frequency by glioblastoma multiforme (GBM) as well as several other tumor types. One approach for targeting this tumor-specific receptor utilizes the cognate ligand, IL-13, conjugated to cytotoxic molecules. However, this approach lacks specificity because the lower affinity receptor for IL-13, IL13R?1, is widely expressed by normal tissues. Here, we aimed to develop and characterize a novel monoclonal antibody (mAb) specific to IL13R?2 for the therapeutic purpose of targeting IL13R?2-expressing tumors. Hybridoma cell lines were generated and compared for binding affinities to recombinant human IL13R?2 (rhIL13R?2). Clone 47 demonstrated binding to the native conformation of IL13R?2 and was therefore chosen for further studies. Clone 47 bound specifically and with high affinity (K(D) = 1.39 × 10(-9) M) to rhIL13R?2 but not to rhIL13R?1 or murine IL13R?2. Furthermore, clone 47 specifically recognized wild-type IL13R?2 expressed on the surface of CHO and HEK cells as well as several glioma cell lines. Competitive binding assays revealed that clone 47 also significantly inhibited the interaction between human soluble IL-13 and IL13R?2 receptor. Moreover, we found that N-linked glycosylation of IL13R?2 contributes in part to the interaction of the antibody to IL13R?2. In vivo, the IL13R?2 mAb improved the survival of nude mice intracranially implanted with a human U251 glioma xenograft. Collectively, these data warrant further investigation of this novel IL13R?2 mAb with an emphasis on translational implications for therapeutic use.

SUBMITTER: Balyasnikova IV

PROVIDER: S-EPMC3436275 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Characterization and immunotherapeutic implications for a novel antibody targeting interleukin (IL)-13 receptor α2.

Balyasnikova Irina V IV Wainwright Derek A DA Solomaha Elena E Lee Gina G Han Yu Y Thaci Bart B Lesniak Maciej S MS

The Journal of biological chemistry 20120709 36

The high affinity interleukin-13 receptor α2 (IL13Rα2) is selectively expressed at a high frequency by glioblastoma multiforme (GBM) as well as several other tumor types. One approach for targeting this tumor-specific receptor utilizes the cognate ligand, IL-13, conjugated to cytotoxic molecules. However, this approach lacks specificity because the lower affinity receptor for IL-13, IL13Rα1, is widely expressed by normal tissues. Here, we aimed to develop and characterize a novel monoclonal anti ...[more]

PMID: 22778273

Similar Datasets

Project description:IntroductionA unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study.MethodsAnti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma.ResultsIn the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo.ConclusionRPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis).FundingAbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript.

Dataset Information

Characterization and immunotherapeutic implications for a novel antibody targeting interleukin (IL)-13 receptor ?2.

Publications

Characterization and immunotherapeutic implications for a novel antibody targeting interleukin (IL)-13 receptor α2.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets